Melatonin reduces intramuscular fat deposition by promoting lipolysis and increasing mitochondrial function

In obesity and diabetes, intramuscular fat (IMF) content correlates markedly with insulin sensitivity, which makes IMF manipulation an area of therapeutic interest. Melatonin, an important circadian rhythm-regulating hormone, reportedly regulates fat deposition, but its effects on different types of adipose vary. Little is known about the role of melatonin in IMF deposition. Here, using intramuscular preadipocytes in pigs, we investigated to determine whether melatonin affects or regulates IMF deposition. We found that melatonin greatly inhibited porcine intramuscular preadipocyte proliferation. Although melatonin administration significantly upregulated the expression of adipogenic genes, smaller lipid droplets were formed in intramuscular adipocytes. Additional investigation demonstrated that melatonin promoted lipolysis of IMF by activating protein kinase A and the signaling of ERK1/2. Moreover, melatonin increased thermogenesis in intramuscular adipocytes by enhancing mitochondrial biogenesis and mitochondrial respiration. A mouse model, in which untreated controls were compared with mice that received 3 weeks of melatonin treatment, verified the effect of melatonin on IMF deposition. In conclusion, melatonin reduces IMF deposition by upregulating lipolysis and mitochondrial bioactivities. These data establish a link between melatonin signaling and lipid metabolism in mammalian models and suggest the potential for melatonin administration to treat or prevent obesity and related diseases.